title: Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease.
abstract: Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer's type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer's disease.
authors.affiliation: Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano, 64/65, 00143, Rome, Italy.
authors.forename: Virve
authors.initials: V
authors.lastname: Cavallucci
authors.forename: Nicola
authors.initials: N
authors.lastname: Berretta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Nobili
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D065095:Calcineurin Inhibitors; D053148:Caspase 3 / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004353:Drug Evaluation, Preclinical; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051528:Guanylate Kinases / Q000096:biosynthesis / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D057907:Post-Synaptic Density / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D065095:Calcineurin Inhibitors; D053148:Caspase 3; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D008734:Methoxyhydroxyphenylglycol; D018696:Neuroprotective Agents; D010768:Phosphoserine; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016559:Tacrolimus; C501447:Dlg4 protein, mouse; C505409:Casp3 protein, mouse; C010117:3,4-dihydroxyphenylglycol